While optimism for the benefits of antiretroviral therapy remain justified, viral reservoirs present a serious impediment to eradicating HIV and indicate that therapy will remain a long-term undertaking. Unfortunately, the response to therapy varies widely. This variability arises because of differences among patients in virologic, immunologic, behavioral, and pharmacologic factors that determine therapeutic success. All antiretroviral agents are presently administered to adults in standard fixed doses. The pharmacologic contribution to the variability in response arises because the same dose does not produce the same systemic and intracellular concentrations in all patients, and anti-HIV effect is related to the concentration of drug in the body. The long-term goal is to develop pharmacologically- and virologically-directed therapy to optimize the efficacy of antiretroviral therapy. We developed concentration-controlled antiretroviral therapy to target specific concentrations and reduce the pharmacologic contribution to variability in response. Work to date has shown that adjusting the doses of antiretroviral agents to achieve target concentrations in plasma is associated with an improved anti-HIV response compared with standard dose therapy. This proposal will extend the paradigm of concentration-controlled therapy to develop pharmacologic intensified regimens for patients experiencing persistent viremia while receiving antiretroviral therapy. Two approaches will be investigated: (1) a regimen that targets concentrations of each antiretroviral drug between the 50-75th percentile of expected concentrations in adults, and (2) a novel regimen where the targets are based upon a desired ratio between phenotypic drug susceptibility (IC90) and the concentrations of pharmacologically-active moieties, specifically intracellular nucleoside triphosphates, and unbound protease and non-nucleoside inhibitors. All subjects will receive adherence counseling and monitoring. The design is straightforward: pharmacologic intensification will be compared with standard dose therapy. The study is randomized, controlled, employs endpoints not subject to bias, and powered to produce results that can be applied to patient care. This work is important and relevant to human health, as it is crucial that persons treated with these medications receive them in a manner that will provide the greatest benefit. This revised application challenges existing paradigms of antiretroviral drug therapy, and builds upon an established foundation to develop novel therapeutic strategies that hold the promise of a new approach to antiretroviral therapeutics.